Glycation of paraoxonase-1 inhibits its activity and impairs the ability of high-density lipoprotein to metabolize membrane lipid hydroperoxides.
OBJECTIVE
High-density lipoprotein (HDL) protects against atherosclerosis development. Defective functioning of HDL in Type 2 diabetes may be one cause of increased cardiovascular disease associated with Type 2 diabetes. HDL modulates low-density lipoprotein and cell membrane oxidation through the action of paraoxonase-1 (PON1), which is one of the major mechanisms by which HDL is anti-atherogenic.


METHODS
We have compared the ability of HDL from Type 2 diabetic patients without coronary heart disease (CHD) (n = 36) to metabolize membrane lipid hydroperoxides with HDL from healthy control subjects (n = 19) and people with CHD but no diabetes (n = 37).


RESULTS
HDL from subjects with Type 2 diabetes and CHD metabolized 20% less membrane hydroperoxides than HDL from control subjects (P < 0.05). The PON1-192RR was least efficient in all the study groups. PON1 was glycated in vivo: (7.5% control, 12% CHD, 17% Type 2 diabetes P < 0.01) with QQ isoforms most glycated. In vitro glycation of PON1 reduced its ability to metabolize membrane hydroperoxides by 50% (P < 0.001); however, glyoxidation reduced it by 80% (P < 0.001). In the control group only there was a significant negative correlation between PON1 activity and the ability of HDL to metabolize membrane hydroperoxides (r = -0.911, P < 0.001).


CONCLUSIONS
HDL from Type 2 diabetic patients without CHD has decreased ability to metabolize membrane lipid hydroperoxides, which could lead to increased susceptibility to cardiovascular disease.
Mastorikou
M
M
Division of Cardiovascular Sciences, University of Manchester, Department of Medicine, Manchester Royal Infirmary, Manchester, UK.
Mackness
B
B
Liu
Y
Y
Mackness
M
M
D043303:Aryldialkylphosphatase / Q000378:metabolism*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013223:Statistics as Topic
D017127:Glycation End Products, Advanced; D008054:Lipid Peroxides; D008075:Lipoproteins, HDL; D043303:Aryldialkylphosphatase